This project explores the biology of remission and relapse in patients with antl-neutrophil cytoplasmic autoantibodies (ANCA) glomerulonephritis and small vessel vasculitis (ANCA disease). The genesis of this exploration stems from the clinical observation that some patients with ANCA disease have 30 years of remission while others have repetitive relapses of significant disease. Ideally, patients destined to relapse should have targeted therapy based on the mechanism responsible for their relapse, and those in remission should be spared immunosuppressive therapy. Although clinical predictors of relapse have been Identified, we have only a rudimentary understanding of the mechanistic basis for relapse and remission. This project takes advantage of our longitudinal ANCA disease cohort to examine relapse and remission from several perspectives. Aim 1 will consider whether relapse is a consequence of aberrant epigenetic regulation of genes encoding the autoantigens myeloperoxidase (MPO) and proteinase 3 (PR3). Building on our basic science findings that epigenetically controlled gene silencing is absent at PR3 and MPO genomic loci In patients with active disease, whether epigenetic silencing of the autoantigen genes is lost during relapse and re-established during remission will be determined. Aim 2 examines whether relapse stems from aberrant B cell function. Is there clonal expansion of the same autoreactive B cell cloneiIn disease onset and relapse, or is relapse a consequence of a new B cell population reactive to different epitopes of MPO and PR3? Whether relapse is due to dysregulated B cells, in the circulation or tissue, that permit production of autoantibodies will be Investigated. In Aim 3, T cell regulation is explored with a focus on T regulatory cells that appear functionally ineffective in relapsing disease. Is relapse caused by an Imbalance in T regulatory cells and proinflamatory Th17 cells that is restored during remission? These analyses will be performed simultaneously and repetitively over time in ANCA disease patients allowing us to gain a mechanistic understanding of the biology of remission and relapse. These observations have broad implications for the care of patients with ANCA disease and for relapsing and remitting autoimmune disease of all types.